Prostate cancer is a significant health problem and the second leading cause of cancer death among men in the United States with an estimated 30,000 deaths every year. The long-term goal of this research project is to develop a safe and effective strategy for prostate cancer prevention. While screening for the activity to stimulate immune cell function by dietary agents using an immune-competent mouse model for prostate cancer, we observed that the dietary agent withaferin-A (WA) significantly induced the activation of natural killer (NK) cells. The dietary agent, withaferin-A is a non-toxic, bioactive compound derived from the plant Withania somnifera, and is traditional medicine widely used in Asia and Africa to boost the immune system. However, the mechanism(s) regulating the functional activation of immune cells by the dietary agents WA remain largely unknown. Based on our preliminary observations, we hypothesize that the dietary agent WA augments NK cell function to inhibit the growth of prostate cancer cells. The rationale for our hypothesis is based on preliminary in vitro studies with WA and on epidemiologic studies indicating that dietary products help to maintain a healthy immune system. Recent studies provide genetic evidence for surveillance of primary tumors by NK cells in the TRAMP (transgenic adenocarcinoma of the mouse prostate), a useful model of prostate cancer. To test our hypothesis, we propose the following specific aims: 1) To determine the mechanism of functional activation of NK cells by WA; and 2) To characterize the mechanism of WA-induced tumoricidal activity by NK cells. The overall objective of this application is to systematically probe into these questions using prostat cancer as a disease model. We have found that the dietary agent WA is able to enhance the functional activity of NK cells. This project will provide a novel paradigm with high impact in the field of prostate cancer prevention given the paucity of information in the literature on the effec of dietary agents such as WA on the tumoricidal activity of NK cells in a prostate cancer model. Successful accomplishment of these studies will provide a rationale for future translational applications using WA to stimulate anticancer properties of NK immune cells for the prevention or delaying of prostate cancer. PUBLIC HEALTH RELEVANCE: This project is designed to characterize the significance of a dietary agent (withaferin-A) in regulating the anti- cancer activity of NK cells for prostate cance prevention. The mechanistic studies will examine the role of cytokines necessary for NK cells activity, and targeted molecules on NK cells engaged in tumoricidal activity using prostate cancer as a model system following withaferin-A treatment.